Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of stroke and myocardial infarction by reducing cholesterol levels and inflammation. More recently, several statins have been shown in animal stroke models to reduce infarct size in a dose-dependent fashion, by both increasing cerebral blood flow through upregulation of endothelial nitric oxide synthase and reducing Inflammation. In a Phase 1B dose escalation and dose-finding study using an adaptive study design, we demonstrated that lovastatin can be administered safely to acute ischemic stroke patients at doses up to 8 times higher (8 mg/kg/day for 3 days) than those currently approved by the FDA. A Phase 2A multicenter, randomized, placebo-controlled trial of short-term high-dose lovastatin therapy at a fixed dose of 640 mg daily for three days in 168 patients with acute ischemic stroke is proposed. Randomization will be stratified by prior statin use. The primary outcome will be safety, defined by development of clinical liver or muscle disease, or liver or muscle enzyme elevations >3X or >10X upper limit of normal, respectively. A safety monitoring committee will review blood pressure, neurological status, and rates of hemorrhagic conversion and infection for evidence of additional or unexpected toxicity. This study will also explore for effects of statin therapy on functional outcome and inflammation. In vitro clot lysis assays requested by FDA will also be performed in Year 1 preparatory to inclusion of patients receiving intravenous or intra-arterial thrombolysis. Data derived from this study will be essential to the planning and design of a Phase 3 trial to test the efficacy of high-dose statin therapy in acute ischemic stroke.
Stroke is a major public health problem in terms of mortality, disability, and cost, and treatments for acute stroke are limited at present. Stroke is very common, particularly among minority populations. The identification of new treatments for acute stroke is an important goal of neurological research, and would have important public health implications.
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